Cancer therapy frequently induces premature menopause in women. The issue of post-therapy quality of life is assuming greater significance as more young women with cancer are cured and live longer. Protection of ovarian functions in women undergoing cancer therapy is the ultimate aim of this proposal. Our completed experiments in rats indicate that luteinizing hormone releasing hormone (LHRH) agonists (LHRHa) protect the ovary and its functions (fertility and hormone secretion) against cyclophosphamide (CTX)-induced ovarian toxicity. Our preliminary results in rhesus monkeys suggest that the same protective effects are attainable in monkeys. As in rats, LHRHa inhibits ovarian mitotic activity in monkeys. We are proposing to develop our very promising results in rhesus monkeys before initiating clinical trials. specifically we shall study the protective effects of LHRHa against CTX-induced ovarian toxicity in rhesus monkeys by: I) Defining the suppressive effects of LHRHa on ovarian mitotic activity and its onset as assessed by tritiated thymidine (3HT) incorporation into ovarian DNA. This will also be correlated with serum FSH, LH, estradiol and progesterone. II) Investigating the mechanisms of ovarian suppressive effects by studying LHRHa-induced changes in bioassayable and radioimmunoassayable gonadotropins, and their ovarian receptors. The direct ovarian effects of LHRHa will be studied in hypophysectomized monkeys. III)Studying the cytotoxic effects of CTX on the monkey ovary by examining follicle number and size in serially sectioned ovaries. In addition, serum FSH, LH, estradiol and progesterone will also be measured; and IV) Evaluating the protective effects of LHRHa against CTX-induced ovarian toxicity using the same parameters described under III. The rhesus monkey reproductive cycle is very similar to that of women. The proposed monkey experiments will yield valuable information, not obtainable otherwise, necessary for a rational design of future clinical trials to protect the ovaries of women undergoing cancer therapy.
